Insights Into the Mechanisms Underlying Anxiety

Most people know what it’s like to worry and feel apprehensive when confronted with an important decision or problem, but when that anxiety becomes severe and won’t go away or comes in repeated episodes, it may reach the level of an anxiety disorder. Up to 40 million Americans have an anxiety disorder in any given year, and it’s thought that only about a third get treatment. New work published in Cell Reports by scientists at the Weizmann Institute of Science may help create new therapeutics for the disorder; they’ve discovered a biological mechanism involved in anxiety.

"Current drugs for anxiety are limited in their efficacy or have undesirable side effects, which also limit their usefulness. Our findings may help overcome these limitations,” said Professor Mike Fainzilber of the Institute's Biomolecular Sciences Department.

For almost twenty years, the Fainzilber lab has investigated how proteins called importins function in neurons. It’s known that they can help move molecules into the nucleus of cells. Dr. Nicolas Panayotis, a postdoctoral fellow in the Fainzilber lab, wanted to know more about the role of importins in the central nervous system.

Panayotis took advantage of five genetically-engineered mouse lines created by Professor Michael Bader's laboratory at the Max Delbrück Center for Molecular Medicine in Berlin; their genes for the importin alpha subfamily had been deleted. The mice were taken through a series of behavioral tests. The researchers found that mice without importin alpha-5 were unique. In stressful situations, they did not display anxiety. In a mouse behavior test, stress might be induced when the mice have to stand out in the open or on an elevated platform.

The researchers compared brain regions that help regulate anxiety in normal mice and the relaxed mice lacking importin alpha-5. Using computational tools, the work identified a gene called MeCP2, which is already known to influence anxiety behaviors. Importin alpha-5 allows MeCP2 to enter neuronal nuclei. An enzyme that influences the production of S1P, a signaling molecule, is affected by nuclear levels of MeCP2. When mice don’t have any importin alpha-5, MeCP2 can’t get into the nucleus, which lowers S1P signaling and reduces anxiety.

"Our findings have opened up a new direction for research into the mechanisms of anxiety," Panayotis said. "If we understand exactly how the circuitry that we've discovered controls anxiety, this may help develop new drugs or direct the use [of] existing ones, to alleviate its symptoms."

Additional work by the team confirmed their results, and they began to look for drugs that could modify these signals. “In follow-up research, we have already identified a number of drug candidates that target the newly discovered pathway,” said Fainzilber.

A drug called fingolimod, a therapeutic for multiple sclerosis, can modulate the activity of S1P. The researchers found that it was able to reduce anxiety in a mouse model - the fingolimod-treated mice behaved similarly to mice that had no importin alpha-5. The scientists also uncovered a finding from a clinical trial of fingolimod - it had a calming effect on participants.

The work also shows why anxiety is a symptom in diseases involving the MeCP2 gene - MeCP2 duplication syndrome and Rett syndrome.

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